Life Sciences Commons^™

The Effect Of Acute And Chronic Arsenic Exposure On Malignant Transformation Of The Human Bronchial Epithelial Cell (Beas-2b), Bandar Almutairy

Wayne State University Dissertations

Arsenic (As3+), a metalloid abundant in the environment, is classified as a group I carcinogen associated with several common human cancers, including cancers in the lung, skin, bladder, liver, and prostate (Wei, Zhang & Tao, 2019b). The mechanisms of As3+-induced carcinogenesis had been extensively studied, and different mechanisms might be involved in various types of cancer (Wei, Zhang & Tao, 2019b). Recent studies showed that exposure to a high dose of arsenic is able to induce lung cancer. Moreover, arsenic activates oncogenic signaling pathways such as MAPKs, EGFR/RAS/RAF, PI3K/AKT, and JNK/STAT3 pathways as well as epigenetic alterations such as miRNAs …

The Arsenic Induced Endoplasmic Reticulum Stress Response Via The Activating Transcription Factor 6 In Human Bronchial Epithelial Beas-2b Cells, Priya Wadgaonkar

Wayne State University Dissertations

Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevantconcentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS-2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic …

The Importance Of Protein Context In Spinocerebellar Ataxia Type 3, Sean Luis Johnson

Wayne State University Dissertations

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) neurodegenerative disorders that includes Huntington's Disease and several other SCAs. SCA3, the most common dominant ataxia in the world, is caused by polyQ tract expansion in the protein, ataxin-3. How SCA3 occurs and how to treat it remain unresolved issues. The primary culprit of toxicity in all polyQ diseases is the glutamine repeat: its abnormal expansion leads to neuronal dysfunction and death. With that said, there is indisputable evidence that the way polyQ-dependent toxicity presents—areas impacted, cellular processes perturbed—is predicated in large part on regions outside …

Deconstructing Brown Adipocyte Neogenesis In Brown And White Adipose Tissue, Rayanne Burl

Wayne State University Dissertations

Global incidence of Type 2 Diabetes (T2D) has reached epidemic proportions, and increasing evidence indicates that dysfunctional adipose tissue is an important contributor to the pathogenesis of T2D. Expanding brown adipocyte (BA) populations within adipose tissues through adrenergic activation improves energy balance and insulin sensitivity. In order to exploit this remodeling of adipose tissue for therapeutic benefit, we need to understand the mechanisms by which adrenergic signaling expand populations of BAs in vivo. These studies utilized single-cell RNA-sequencing and transgenic mouse models, in combination with single-molecule fluorescence in situ hybridization (smFISH) and immunoistochemical analysis, to study BA neogenesis in vivo. …

Kinase-Catalyzed Labeling To Identify Kinase-Substrate Pairs Using Γ-Phosphate Modified Atp Analogs, Rachel Beltman

Wayne State University Dissertations

Post-translational modifications (PTMs) are responsible for a variety of cellular processes. One such PTM is protein phosphorylation, which is catalyzed by kinases. Kinase enzymes play important roles in cellular signaling pathways, but dysregulation of kinase-mediated events results in the formation of diseases, which make kinases favorable drug targets. To uncover the role kinases play in the development of diseases, kinase-mediated cellular events need to be better understood. The current gap in the field is the lack of tools available to identify the kinase that is responsible for specific phosphorylation events within the cell. To improve the gap in the field, …

Study Of Zyomogen Granule Movement Along Actin Filaments Using A Single Beam Optical Trap, Justin James Raupp

Wayne State University Dissertations

Zymogen granules are enzymatic vesicles in the pancreas. The surface of these zymogen granules (ZGs) has several different kinds of myosin molecules, such as myosin 1c, 6, 5c, and 7b. These molecular motors may contribute to ZG transportation in cells. To understand the molecular motors involved in the vesicle trafficking, we observed the in vitro motility of purified ZGs from rat pancreas and examined the stepping behavior and force that is generated using a single beam optical trap. To be involved in trafficking, molecular motors have certain characteristics, a high duty ratio and the ability to move continuously along actin …

Impacts And Dispersal Of Invasive Bivalves, Dreissena And Corbicula Spp., On Stream Benthic Communities, Darrin Scott Hunt

Wayne State University Dissertations

Asian clams (Corbicula spp.), zebra and quagga mussels (Dreisenna spp.) have invaded and spread throughout North American surface waters. Corbicula and Dreisenna species bio foul aquatic systems, occupy benthic substrates and degrade environments through shell deposition. I explored how Dreissena and Corbicula invasions affect benthic fish and macroinvertebrate communities, and examine how their impacts differ between urban and rural systems, and temperate and tropical climates. Macroinvertebrate and fish communities were evaluated at sites with increasing shell densities in the Rouge, and Huron rivers (MI, USA) using the United States Environmental Protection Agency’s Rapid Bioassessment Protocols (RBP). Urban and rural macroinvertebrate …

The Role Of Biomaterial Substrate In Stem Cell Fate Determination, Zhenjie Liu

Wayne State University Dissertations

The physical cues, which included topography, stiffness, and mechanical forces, can influence the stem cell renewal, differentiation, and maturation in vivo and in vitro. The nano-topography of the ECM can stimulate the neural differentiation of the stem cells, while the micro-topography of the ECM can guide the neurite outgrowth. However, the role and functional size of the micro- and nano-topography in the stem cell fate determination is not clear yet. To study this aim, two biomaterial based aligned fiber platforms (ACMFP and ASMFP) were designed, fabrication and evaluated to cover the micro-, submicro-, and nano-fiber topography, which used to study …

A Multispecies Perspective Into Dietary Genetic Adaptations And Ancient Migration In The Peruvian Andes, Kelsey Jorgensen

Wayne State University Dissertations

Successful adaptation to the high-elevation Andes would have required both cultural and biological adaptations by early human populations. These past adaptations continue to shape the evolutionary outcomes of both humans and non-human species today. A multispecies perspective was used to examine how humans and non-human creatures, specifically insects, were shaped by past human adaptations. This dissertation asked two primary questions: 1) Given the importance and evolutionary history of potato consumption in the Peruvian Andes, is a genetic adaptation to better digest potato starch detectable in present-day Peruvians? and 2) Using the Andean Potato Weevil (APW) phylogeny as a proxy, what …

Identifying Biologically Relevant Mechanisms And Biomarkers Using Novel Bioinformatics Methods, Samer Hanoudi

Wayne State University Dissertations

There is a tremendous need to analyze molecular and patient clinical data to identify biomarkers, biological mechanisms, or to simply classify samples accurately. Issues such as: i) limited tools to diagnose many diseases, ii) not considering biological interactions, or iii) damaged DNA samples could cause a challenge in identifying valuable insights. In this work, I try to address these issues by developing different bioinformatic frameworks.First, I present three frameworks to identify i) Sarcoidosis biomarkers, ii) Tuberculosis biomarkers and iii) Cystic fibrosis (CF) biomarkers. I identified Sarcoidosis biomarkers I applied them to classify Sarcoidosis samples from non-Sarcoidosis (healthy controls, Tuberculosis, and …

The Probiotic Effect Of Clostridium Cochlearium Is Associated With Significant Change In Short-Chain Fatty Acid Metabolism And Gut Microbiota, Qing Ai

Wayne State University Dissertations

The prevalence of obesity is rising steadily across the world, which increases the risk of many metabolic diseases and life-threatening illnesses. A specific strain, Clostridium cochlearium (C. cochlearium), reported as a butyrate producer, could have potential probiotic effects against obesity. The objective of this study was to evaluate the effects of dietary supplementation of C. cochlearium on a high-fat diet-induced obese (DIO) mouse model. The 16S rRNA sequencing of mice gut microbiome was performed at the end of the experimental period to identify the changes in gut microbial composition, investigate possible functional genes, and elucidate potential mechanisms. Thirty-six C57BL/6 6-8 …

Health And Nutrition Status Of Hemodialysis Patients During Ramadan In Saudi Arabia., Bayan Mansour Tashkandi

Wayne State University Dissertations

During Ramadan R month, Muslims abstain from eating, drinking, and medication from sunrise to sunset, and this causes some changes in their lifestyle and often eating habits (quantity and quality). These changes could lead to affect their health and nutritional status. Among Hemodialysis (HD) patients, malnutrition is common, and it is associated with mortality. Some HD patients opt to fast R which could have an impact on their nutritional and health status. Thus, the primary objective of this study was to document nutritional changes before, during, and after Ramadan on biochemical and health parameters in HD patients. A prospective cohort …

Substrate Profiling Of The Epigenetic Erasers Hdac1 And Lsd1, Herath Mudiyansela Gedara Kavinda Eranga Herath

Wayne State University Dissertations

Regulators of chromatin structure have emerged as a key driver of transcriptional responses inside the cell. Two such groups of regulators, histone writers and erasers; the proteins, that add or remove histone post translational modifications (PTMs), have become the central players in chromatin structure. Thus, the aberrant expression of writers and erasures is a hallmark in human diseases. For example, overexpression of the erasures histone deacetylase1 (HDAC1) and lysine specific demethylase1 (LSD1) had been reported in many cancers. Currently, HDAC inhibitors have been used successfully for cancer treatment and several inhibitors targeting LSD1 are in clinical trial. To date, apart …

Therapeutic Dual-Targeting Of Cytosolic And Mitochondrial One-Carbon Metabolism, Aamod Sanjeev Dekhne

Wayne State University Dissertations

One-carbon metabolism (1CM) is compartmentalized in the mitochondria and cytosol and generates a host of metabolites critical to tumor propagation. Although drug-targeting of cytosolic 1CM remains a clinically-relevant mainstay, development of clinically-useful agents targeting mitochondrial 1CM remains elusive. Of particular pharmacological interest is the mitochondrial 1CM enzyme, serine hydroxymethyltransferase2 (SHMT2). SHMT2 expression correlates with the oncogenic phenotype in lung, colon, breast, glioma, and liver cancer and, overall, is the fifth-most differentially expressed metabolic enzyme in cancer cell versus normal tissue. Despite the unequivocal oncogenic importance and therapeutic potential of SHMT2, there are no clinically relevant (i.e. active in vivo) inhibitors …

Protein Phosphatase 2a In Metformin’S Action In Primary Human Skeletal Muscle Cells, Aktham H. Mestareehi

Wayne State University Dissertations

Diabetes is a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both. Diabetes is associated with damage, dysfunction, and failure of various organs, such as the eyes, heart, kid-neys, and brain. Diabetes is mainly classified into type 1 (T1DM) and type 2 diabetes (T2D). Diabetes affects more than 34 million people in the USA (about 1 in 10) and more than 90% of diabetic patients have type 2 diabetes (T2D). Insulin resistance is a main characteristic feature of type 2 diabetes. Skeletal muscle insulin resistance is con-sidered to be the primary defect …

Characterization Of Clostridium Cochlearium As A Potential Probiotic For Obesity Management, Paba Edirisuriya

Wayne State University Dissertations

ABSTRACTCHARACTERIZATION OF CLOSTRIDIUM COCHLEARIUM AS A POTENTIAL PROBIOTIC FOR OBESITY MANAGEMENT

ByPABA EDIRISURIYA MAY 2021 Advisor: Dr. Kequan Zhou Major: Nutrition and food science Degree: Doctor of Philosophy Emerging evidence indicates that manipulation of gut microflora is a potential therapeutic approach for managing obesity. Probiotic effects on host weight reduction have repeatedly been revealed through previous studies. Clostridium cochlearium is a butyrate-producing, spore-forming bacteria that have been reported to present in the mammalian gut. Our simulated Invitro digestion model revealed that C. cochlearium could survive in the unfavorable conditions of the human gastrointestinal tract, including low pH (pH2), high bile …

Cardio-Renal Mechanisms Of Fructose-Induced Salt-Sensitive Hypertension, Peter Eric Levanovich

Wayne State University Dissertations

Dietary consumption of fructose facilitates increased intestinal fluid absorption and renal sodium reabsorption, thereby increasing fluid retention. The net result of this is a sustained increased in extracellular fluid volume that leads to states of hypervolemia and subsequent hypertension. Simultaneously, arterial pressure is being elevated by increased autonomic drive stemming from the sympathetic nervous system and various other endovascular proteins that induce vasoconstriction. Under these conditions, the addition of high dietary sodium promotes hypertension prior to the development of significant metabolic disturbances; the subtlety of which may go unnoticed by patients for prolonged periods. While much is understood regarding the …

Clinical Significance, Functional Role And Molecular Mechanism Of 2’-O-Methyltransferase Ftsj3 In Promoting Cancer Progression, Morenci Manning-Powell

Wayne State University Dissertations

2’-O-methylation (2’-O-Me), one of the most common modifications within RNA, has multiple roles in modulating RNA structure, stability, and interactions, as well as gene transcription and translation. We previously performed integrative genomic and transcriptomic analysis of 58 RNA methyltransferases, and identified FTSJ3 (FtsJ RNA 2ʹ-O-methyltransferase 3) as significantly amplified/overexpressed in breast cancer. Knockdown of FTSJ3 inhibits breast cancer cell growth in vitro. However, the clinical significance, functional role, and molecular mechanism of FTSJ3 in human cancer remains to be elucidated. In the present study, we first analyzed the differential mRNA and protein expression of FTSJ3 between tumor and normal tissues …

Mnrr1: Understanding The Role Of A Novel Mitochondrial-Nuclear Regulator, Stephanie L. Gladyck

Wayne State University Dissertations

Mitochondria are complex organelles that generate most of the energy required to sustain life and function in metabolic and signaling pathways required to maintain cellular homeostasis. MNRR1 (mitochondrial nuclear retrograde regulator 1 or CHCHD2) is a small, bi-organellar twin CX9C protein that is emerging as an important regulator of mitochondrial function, apoptosis, and cellular stress by participating in mitochondrial-nuclear crosstalk. Our lab has previously shown that in the mitochondria, MNRR1 regulates complex IV (Cytochrome c oxidase or COX) and is able to finetune the oxidase function through phosphorylation status. We have also shown that during stress, mitochondrial MNRR1 levels deplete, …

Modulation Of Pharyngeal Health In Bacterial Diet-Dependent Survival, Deniz Sifoglu

Wayne State University Dissertations

ABSTRACT

MODULATION OF PHARYNGEAL HEALTH IN BACTERIAL DIET-DEPENDENT SURVIVAL

by

DENIZ SIFOGLU

August 2021

Advisor: Dr. Joy Alcedo Major: Biological Sciences Degree: Doctor of Philosophy Both diet and bacterial microbiome modulate insulin signaling, which regulates key physiological processes that are important for survival. However, the mechanisms through which diet and the microbiome modulate insulin signaling remain unclear. To understand these mechanisms, I turned to the nematode worm C. elegans, whose diet consists of different types of bacteria. Like humans and other animals, C. elegans has to modulate its responses to its diet and to bacteria to optimize its survival. Because …

Evolutionary Ecology Of The Native Johnny Darter (Etheostoma Nigrum) And The Invasive Round Goby (Neogobius Melanostomus): A Genomic Perspective, Abby Joyce Wicks

Wayne State University Dissertations

Round goby (Neogobius melanostomus) is an invasive fish present in all five Great Lakes and is becoming increasingly common in their tributaries. Johnny darter (Etheostoma nigrum) is a native species that often coexists with round goby. Here, I use traditional population genetic methods and genomic tools to explore the evolutionary ecology of these species. First, historic factors are addressed as a source of variation in study populations by characterizing patterns of mitochondrial DNA variation throughout Lower Michigan. Round goby populations were largely homogenous and exhibited no evidence of overarching historical genetic structure, consistent with the recent invasion and rapid expansion …

Evaluating Historical Paradigms Of Sterility In Perinatal Microbiology And Ramifications For Pregnancy Outcomes, Jonathan Greenberg

Wayne State University Dissertations

Next-generation sequencing technologies, especially 16S rRNA gene and metagenomic sequencing have allowed investigations of low microbial biomass tissues of the human body. While these sequencing methodologies have provided large amounts of reliable data for higher microbial biomass sites, such as the mouth, intestine, and vagina, tissues of low microbial biomass sites are subject to specific caveats that were not appropriately considered in early investigations of these sites. Low microbial biomass sites of particular interest have included those of the reproductive and urinary systems. Utilization of DNA sequencing methodologies have allowed researchers to challenge existing paradigms of sterility around these sites …

Addressing The Issue Of Missing Heritability: The Importance Of Apoptosis In Hereditary Breast And Ovarian Cancer And Functional Assessment Of Tp53i3-S252*, Sophia Chaudhry

Wayne State University Dissertations

A quarter of all cases of ovarian cancer (OVCA) cases are due to inherited factors. However, much of the genetic risk remains unknown. We have previously established the importance of whole exome sequencing to answer the question for missing heritability. We identified clinically actionable and novel risk loci in the DNA repair and cell cycle regulation pathways by assessing a cohort of women diagnosed with OVCA, wildtype for BRCA1/BRCA2 and suspected to be hereditary due to family history of breast cancer/OVCA. Equally as important was the exploration and discovery of novel risk loci in the apoptosis pathway. A total of …

Timing And Duration Of Folate Restriction Differentially Impacts Colon Carcinogenesis., Ali M. Fardous

Wayne State University Dissertations

Colorectal cancer (CRC) constitutes a major burden on the healthcare system as the second most commonly diagnosed cancer in the developed world. Dietary folate is considered an important modulator of colorectal cancer. Folate restriction has been implicated in increasing CRC incidence by disrupting nucleotide synthesis, Impacting DNA methylation and inducing genetic instability. Our research shows that the timing and duration of dietary folate restriction can differentially impact Colorectal cancer initiation. Acclimating mice to folate restriction for 8 weeks results in a reduced number of preneoplastic lesions compared to mice placed of folate restriction for 1 week prior to initiating the …

Computational Analysis Of Oxidative Stress In Endothelial Dysfunction: Insights On The Role Of Tetrahydrobiopterin, Ascorbate And Glutathione, Sheetal Kedar Panday

Wayne State University Dissertations

Oxidative stress and endothelial dysfunction are reported in the cardiovascular and neurovascular diseases. Oxidative stress is caused due to an increase in the generation of reactive oxygen (ROS) and nitrogen species (RNS) and incapacity of antioxidant systems to eliminate ROS and RNS. Endothelial dysfunction is characterized by a reduction in nitric oxide (NO) bioavailability. NO is constitutively produced by enzyme endothelial nitric oxide synthase (eNOS). A reduction in tetrahydrobiopterin (BH4), which is an essential cofactor of eNOS, can lead to eNOS uncoupling. There is complex interplay between the ROS/RNS and antioxidant system underlying pathophysiologies of vascular diseases, however our quantitative …

Termination-Independent Role Of Rat1 In Cotranscriptional Splicing In Budding Yeast, Zuzer Hakimuddin Dhoondia

Wayne State University Dissertations

Rat1 is a 5′→3′ exoribonuclease in budding yeast belonging to the XRN-family of nucleases. It is a highly conserved protein with homologs being present in fission yeast, flies, worms, mice and humans. Rat1 and its homolog in metazoan have been shown to function in multiple facets of RNA metabolism. In this study, we report a novel role of Rat1 in splicing of pre-mRNA in budding yeast. In the absence of the functional Rat1 in the nucleus, an increase in the level of unspliced transcripts was observed in yeast cells. Strand-specific TRO analysis revealed that the accumulation of unspliced transcripts upon …

The Dynamics Of Life And Death: Mitochondrial Fragmentation, Mitophagy, And Swelling During Neuronal Ischemia/Reperfusion Injury, Anthony Roy Anzell

Wayne State University Dissertations

Ischemic brain injury caused by cardiac arrest or stroke continue to be leading caused of death and disability in the U.S. While restoration of blood flow is necessary to salvage ischemic tissue, reperfusion paradoxically exacerbates injury via the production of reactive oxygen species, which, damage mitochondria and induce cell death. Therefore, it is critical to have stringent quality control mechanisms to ensure a healthy mitochondrial network. Mitochondrial fragmentation has been well characterized in the progression of ischemia/reperfusion and its association with cell death. Conversely, the role of mitophagy has been controversial regarding whether upregulation of mitophagy serves as a restorative …

The Relationship Between Excessive Folic Acid Intake And Genome Instability In Human Lymphocytes, Khadijah Ibrahim Alnabbat

Wayne State University Dissertations

Since its synthesis in 1945, Folic acid (FA) is widely used as a supplement/additive to our food due to its stability and high bioavailability. FA is proposed to alleviate anemia and reduce neural tube defects (NTD). As a provitamin, FA is activated through a two-step reaction catalyzed by dihydrofolate reductase (DHFR) in the folate metabolism pathway. FA activation rate is found to be slow in humans. After the implementation of mandatory food fortification program of grain and grain products with folic acid in the USA in 1998, many concerns have been raised about the unintended deleterious consequence of exposing the …

Development Of Rat Head Finite Element Model And Tissue Level Biomechanical Threshold For Traumatic Axonal Injury, Runzhou Zhou

Wayne State University Dissertations

Traumatic brain injury (TBI) is caused by local tissue deformation at the time of trauma, leading to neurological dysfunction. In the United States alone, 2.87 million people sustain a TBI each year, of which one-fifth results in death. Traumatic axonal injury (TAI) is a well-recognized consequence of every fatal head injury and more than 85% of vehicular crash-related blunt head injuries. The most common and important pathologic feature of TBIs are multifocal changes to axons in the white matter produced by rapid head acceleration/deceleration during a traumatic event with consequent local shear/tension on neural tissue and axons contributing to secondary …

Nutrition And Health Status Of Hemodialysis Patients In Dhaka, Bangladesh, Tanjina Rahman

Wayne State University Dissertations

Methods to identify patients at risk for End stage renal disease (ESRD) are a high priority in Bangladesh, where kidney transplants/dialysis options are limited and costly. Every year, 35,000 to 40,000 people reach ESRD in Bangladesh, but currently available facilities can hardly accommodate only 9000 to 10,000 new patients with twice weekly dialysis and the remaining 66% have no access to any kind of renal replacement therapy (RRT) in the form of dialysis or transplantation. Nutrition is an important factor in maintaining good health of hemodialysis patients. However, data on nutritional status of Bangladeshi dialysis patients is limited and is …